Acridine-based (thio)semicarbazones and hydrazones: Synthesis,in vitro urease inhibition,molecular docking and in-silico ADME evaluation

Urease is a bacterial enzyme that is responsible for virulence of various pathogenic bacteria such as Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Ureaplasma urealyticum, Helicobacter pylori and Mycobacterium tuberculosis. Increased urease activity aids in survival and colonization of pathogenic bacteria causing several disorders especially gastric ulceration. Hence, urease inhibitors are used for treatment of such diseases. In search of new molecules with better urease inhibitory activity, herein we report a series of acridine derived (thio)semicarbazones (4a-4e, 6a-6l) that were found to be active against urease enzyme. Molecular docking studies were carried out to better comprehend the preferential mode of binding of these compounds against urease enzyme. Docking against urease from pathogenic bacterium S. pasteurii was also carried out with favorable results. In silico ADME evaluation was done to determine drug likeness of synthesized compounds.     

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.     

肠道真菌研究进展

摘要：肠道真菌是肠道微生物的重要组成部分，在肠道正常菌群中所占比例极小，主要包括假丝酵母属（Candida）、隐球酵母属（Cryptococcus）、青霉属（Penicillium）、曲霉属（Aspergillus）、红酵母属（Rhodotorula）等，对维持肠道微生态稳态和机体健康具有重要作用，也与抗生素相关性腹泻（AAD）、乙型肝炎、炎症性肠病（IBD）等疾病的发病机制息息相关。本文主要总结了目前已发现的肠道真菌属及其对人体的影响机制以及肠道真菌相关的研究方法，为肠道真菌在疾病的诊断和治疗方面的进一步研究提供依据与思路。     

The study of agglutination of trypsin-treated sheep red cells by Corynebacterium diphtheriae strains

Abstract 620 Corynebacterium diphtheriae strains from 472 sick and healthy persons were studied for their adhesive activity (AA) in direct agglutination of trypsin-treated sheep erythrocytes. Toxigenic strains had more active AA than non-toxigenic ones which was not dependent on the presence of toxin in the culture. Neither biotype nor serotype of the strains correlated with their AA. Several lysotypes among toxigenic and non-toxigenic strains were more active than others. Toxigenic strains from patients had higher AA than those from carriers. Both toxigenic and non-toxigenic strains isolated from the prolonged carriers possessed the highest AA. It was concluded that AA measured in this way was an important colonization factor for all diphtheria strains and a pathogenicity factor for toxigenic strains.     

呼吸机相关性肺炎患者病原菌分布及IL 35的炎症控制机制

目的探讨呼吸机相关性肺炎(VAP)患者病原菌分布及白细胞介素35(IL-35)的炎症控制机制。方法回顾性分析2016年12月至2018年12月在我院重症监护病房(ICU)行机械通气的152例患者的临床资料,根据是否发生VAP将其分为VAP组(n=70)和对照组(n=82)。收集VAP患者痰液进行细菌培养及药敏实验,检测并比较两组患者外周血单个核细胞(PBMCs)中CD4~+CD25~+CD127dim/-调节性T细胞(Tregs)比例及血清中白细胞介素35(IL-35)、肿瘤坏死因子α(TNF-α)、干扰素-γ(IFN-γ)水平;同时检测并比较经佛波酯和重组人IL-35刺激后的Tregs细胞培养液上清中IL-35、IFN-γ、TNF-α水平。结果 70例VAP患者共检出病原菌128株,其中革兰阴性菌占82.81%,革兰阳性菌占14.84%,真菌占2.34%。鲍曼不动杆菌对头孢西丁的耐药率最高,对头孢哌酮的耐药率最低。铜绿假单胞菌对头孢西丁的耐药率最高,对亚胺培南的耐药率最低。肺炎克雷伯菌对头孢西丁的耐药率最高,对头孢哌酮的耐药率最低。VAP组患者PBMCs中CD4~+CD25~+CD127dim/-Tregs比例及血清中IL-35、IFN-γ、TNF-α水平显著高于对照组(t=12.675、36.631、13.464、8.482,均P0.001)。经重组人IL-35刺激后的Tregs细胞培养液上清中IL-35水平显著高于佛波酯刺激后(t=8.886,P0.001)。经重组人IL-35刺激后的Tregs细胞培养液上清中IFN-γ、TNF-α水平显著低于佛波酯刺激后(t=14.091、7.588、均P0.001)。结论呼吸机相关性肺炎病原菌以革兰阴性菌为主,呈现多药耐药性,临床应合理使用抗菌药物以防治呼吸机相关性肺炎。IL-35可通过调控Tregs功能降低促炎因子分泌从而在呼吸机相关性肺炎发病过程中发挥抗炎症作用,提示IL-35可能为呼吸机相关性肺炎的治疗提供新的方向。     

Observation by electron microscopy of a gregarine parasite of Antarctic krill: its histological aspects and ecological explanations

Antarctic krill are parasitized by gregarines (Phylum Apicomplexa, Class Sporozoea, Order Eugregarinida), which were observed in this study by light, scanning, and transmission electron microscopy. Eighty seven percentage of the krill examined (n = 93) were infected with the parasites in the cephalin stage, which were regularly found in the hind-gut epithelium of their host. Cephalins were found attached to the epithelium, and then were liberated into the intestinal lumen. The gamont stage, which follows the cephalin stage, was found in the intestinal lumen, as well as the diverticulum of mid-gut gland. However, gamonts found in the mid-gut gland were considerably larger and elongated in comparison with those in the intestinal lumen. Gamonts in the diverticulum appear to damage microvilli, which are involved in the uptake of digested nutrients and secretion of various enzymes. Therefore, elevated infestation of this parasite in the mid-gut gland may have a significant impact on the nutritional state of the Antarctic krill host.     

The phosphatome of opportunistic pathogen Candida species

Several Candida species, the best known example of which is Candida albicans, are opportunistic human pathogens that are responsible for frequent nosocomial infections. A worrisome aspect of the currently available treatments of candidemia is the steady development of resistance to antifungals among these potentially life threatening fungi. Under these circumstances the search for novel drug targets is a well justified research direction. We propose that the principles of signal transduction therapy by targeting protein phosphatases can be adopted as these enzymes carry out important physiological functions in Candida. We demonstrate that C. tropicalis, C. albicans, C. dubliniensis, and S. cerevisiae exhibit the largest repertoire of protein phosphatases among the investigated fungi. Together with other opportunistic pathogen Candida species and the members of the Saccharomycetales order, they expanded their phosphatome by repeated gene duplications. We noted that evolution generated a set of fungus specific phosphatases which can be targeted without the danger of causing undesirable side effects in the human body. Based on the conflicting criteria of effectiveness and selectivity, we identified and characterized 7 phosphatases that are potent virulence determinants and may be utilized as potential antifungal drug targets.     

Free-living amoebae and other neglected protistan pathogens: Health emergency signals?

Protistan parasites have an undisputed global health impact. However, outside of a few key exceptions, e.g. the agent of malaria, most of these infectious agents are neglected as important health threats. The Symposium entitled “Free-living amoebae and neglected pathogenic protozoa: health emergency signals?” held at the European Congress of Protistology in Rome, July 2019, brought together researchers addressing scientific and clinical questions about some of these fascinating organisms. Topics presented included the molecular basis of pathogenicity in Acanthamoeba; genomics of Naegleria fowleri; and epidemiology of poorly diagnosed enteric protistan species, including Giardia, Cryptosporidium, Blastocystis, Dientamoeba. The Symposium aim was to excite the audience about the opportunities and challenges of research in these underexplored organisms and to underline the public health implications of currently under-appreciated protistan infections. The major take home message is that any knowledge that we gain about these organisms will allow us to better address them, in terms of monitoring and treatment, as sources of future health emergencies.